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The 2025 Lasker similar to DeBakey Clinical Medical Research Award has been given to Michael Welsh, Jesus (Tito) Gonzalez, and Paul Negulescu for their key roles in developing a novel treatment for cystic fibrosis (CF)-a three-drug combination that saves the lives of people with this lethal genetic disease [D. Keating etal., N. Engl. J. Med. 379, 1612-1620 (2018)]. The disease is caused by mutations that disrupt the function of a gene known as CF Transmembrane Conductance Regulator which encodes a chloride channel expressed in epithelial cells including the lung. Collectively the three recipients were responsible for the development of novel high-throughput drug screens that led to the development of the new drugs. Welsh is a pulmonologist who played a key role in understanding the physiology and pathophysiology of the disease. Gonzalez is a physical organic chemist who developed a novel technology that enabled robust high-throughput screens for drugs that correct the channel defects. Negulescu led a group of extremely talented biologists, chemists, and physicians who built on these advances to develop novel three-drug combinations that have miraculous benefits for the majority of afflicted patients. This advance represents a true milestone in medicine and fulfills a dream of research scientists and families-the conversion of a fatal disease into a fully treatable one. It is also a stunning example of the power of medical research to save people's lives.

We recently reported the discovery of TDI-015051, a first-in-class small-molecule inhibitor of the SARS-CoV-2 guanine-N7 methyltransferase nonstructural protein 14 (NSP14). NSP14 plays a critical role in viral RNA cap synthesis and its inhibition represents a novel antiviral approach. Utilizing systematic structure-activity relationship studies, potent non-nucleoside-based inhibitors with single-digit nanomolar cellular activity were identified from an HTS hit lacking cellular activity. Thermal shift assay data and available crystal structures led us to develop a model of the novel inhibitory ternary complex (NSP14, SAH, inhibitor), which was validated with a crystal structure of the complex. The advances described here enabled a successful proof-of-concept study that validated SARS-CoV-2 NSP14 as a novel drug target for COVID-19 and represent the first demonstration of pharmacological inhibition of viral methyltransferases as a viable avenue for an antiviral therapeutic.

Corynebacterium bovis causes skin disease in immunocompromised mice and possibly rats. In 2022, scaly skin and mortality were observed in 7-to 11-d-old neonates (n = 8) from a primiparous Armenian (Nothocricetulus migratorius) hamster breeding pair in a newly established colony. C. bovis was detected by culture and PCR, and affected animals had moderate to severe acanthotic, hyperkeratotic lesions with intralesional C. bovis confirmed by in situ hybridization. Intrafollicular Demodex cricetuli mites, an ectoparasite found in all laboratory-maintained Armenian hamsters, were also identified in affected animals. To elucidate the role of D. cricetuli on C. bovis-associated disease and maintain adult hamsters without the need for sustained mite treatment, a D. cricetuli-free colony was generated by treating breeding pairs and their 1-to 3-d-old neonates with topical fluralaner (35 mg/kg), and a prospective study was undertaken to compare C. bovis-associated pup mortality in D. cricetuli-free and D. cricetuli-infested hamsters. During the ensuing 22 mo, 4 of 96 (4.2%) litters born exhibited C. bovis-associated disease and/or mortality. The litters were born to 4 different nulliparous breeding pairs (n = 47, 9%). Of the 4 affected litters, 2 were D. cricetuli-infested while 2 were D. cricetuli-free. C. bovis was routinely cultured with a variable bacterial burden that had no association with mortality or skin lesion severity from all hamsters, independent of their D. cricetuli status. The severity of histologic pathology appeared to correlate with clinical presentation and mortality in neonates. Whole genome sequencing was performed on 4 hamster C. bovis isolates, which revealed a close genetic association among the isolates as well as with previously characterized mouse and rat C. bovis isolates.

In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC50) below 10 mu M. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.

Scientists can contribute to society in numerous ways. Some scientists discover new biological principles and found entirely new fields. Some scientists are inspiring mentors and create the next generation of inclusive lab leaders. Some scientists are entrepreneurs who develop clinically effective therapeutics. Some scientists are trusted advisors to government and pharmaceutical companies. Some scientists are visionary institutional leaders who build new departments. From this menu of activities, most scientists select two or at most three. It is exceedingly rare for a single scientist to excel in all of these areas, consistently, over the course of a career. Lucy Shapiro is this extraordinary scientist. She founded the field of bacterial cell biology and trained the next generation of microbiologists, launched biotech companies to develop new antifungal drugs, served as an unofficial advisor to two presidential administrations and numerous companies, institutions, and foundations, and built and led successful academic departments. The 2025 Lasker similar to Koshland Special AchievementAward in Medical Science is awarded to Lucy Shapiro "for a 55-y career in biomedical science-honored for discovering how bacteria coordinate their genetic logic in time and space to generate distinct daughter cells; for founding Stanford's distinguished Department of Developmental Biology; and for exemplary leadership at the national level."

Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediated synapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on the release of Wnts from microglia downstream of neuron-to-microglia fractalkine ligand-receptor (CX3CL1-CX3CR1) signaling. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and that this signaling is upregulated in several disease contexts.

Biallelic pathogenic variants in the essential DNA repair gene BRCA2 cause Fanconi anemia complementation group D1. Patients in this group are highly prone to develop embryonal tumors, most commonly medulloblastoma arising from the cerebellar granule cell progenitors (GCPs). GCPs undergo high proliferation in the postnatal cerebellum under Sonic Hedgehog (SHH) activation, but the type of DNA lesions that require the function of the BRCA2 to prevent tumorigenesis remains unknown. To identify such lesions, we assessed both GCP neurodevelopment and tumor formation using a mouse model with deletion of exons three and four of Brca2 in the central nervous system, coupled with global Trp53 loss. Brca2 Delta ex3-4;Trp53-/- animals developed SHH subgroup medulloblastomas with complete penetrance. Whole-genome sequencing of the tumors identified structural variants with breakpoints enriched in areas overlapping putative G-quadruplexes (G4s). Brca2-deficient GCPs exhibited decreased replication speed in the presence of the G4-stabilizer pyridostatin. Pif1 helicase, which resolves G4s during replication, was highly upregulated in tumors, and Pif1 knockout in primary medulloblastoma tumor cells resulted in increased genome instability upon pyridostatin treatment. These data suggest that G4s may represent sites prone to replication stalling in highly proliferative GCPs and without BRCA2, G4s become a source of genome instability. Tumor cells upregulate G4-resolving helicases to facilitate rapid proliferation through G4s highlighting PIF1 helicase as a potential therapeutic target for treatment of BRCA2-deficient medulloblastomas.

BackgroundWe sought to determine the comparative effectiveness of two strategies for assigning care coordinators to people living with dementia (PLWD) and their caregivers.MethodsWe conducted a pragmatic randomized clinical trial embedded in a Medicare accountable care organization (ACO) in New York, NY in 2022-2024. We included community-dwelling PLWD >= 65 years who were attributed to the ACO and had highly fragmented ambulatory care in the previous year (reversed Bice-Boxerman Index >= 0.86). The trial compared usual care (assigning care coordinators to PLWD after hospital discharge) to usual care plus proactive outreach, which assigned care coordinators to PLWD if they or their caregivers reported difficulty with care coordination on a telephone survey. Participants were followed for the combined outcome of emergency department (ED) visit or hospitalization.ResultsAmong the 385 PLWD in the trial, the mean age was 82.6 years (SD 6.9), and 56.4% were female. Overall, participants had had a mean of 14.9 ambulatory visits to 8.9 different providers the previous year. The acceptance rate of care management was higher in the control group (73.7%) than in the intervention group (38.0%). Care coordinators were ultimately assigned to 14 of 192 PLWD in the control group (7.3%) and 19 of 193 PLWD in the intervention group (9.8%). The intention-to-treat analysis (N = 385) found a trend toward fewer ED visits in the intervention group (0.14 ED visits per 100 person-days alive vs. 0.18 ED visits per 100 person-days alive, p = 0.07) but no difference in the combined outcome of ED visit or hospitalization (p = 0.71).ConclusionAlthough the particular intervention we tested was not more effective than usual care, this trial is novel in that it used highly fragmented care as an inclusion criterion and shows that more work is needed to address fragmented care among PLWD.

Background/Objectives: While single variants may have only small effects on common heritable traits like schizophrenia, methods for combining such effects over multiple variants have been proposed for more than 30 years. The currently favored approaches are polygenic risk scores. Their main aim is the genetic prediction of phenotypes. Methods: To accommodate the inherent genetic heterogeneity between males and females, we separated them into two independent datasets and in each developed allelic polygenic risk scores. We focused on variants with high predictability rather than high statistical significance and derived a statistical test to assess the significance of results obtained in one sex and replicated in the other sex. Results: As few as 5000 highly predictive variants achieved accuracy exceeding 95% in each of males and females, and only 2.8% and 3.3% of cases and controls were misclassified in females and males, respectively. Conclusions: Our allelic polygenic risk scores are based on individual genotypes rather than summary statistics and produce highly accurate, cross-validated phenotype predictions. Although variants were originally selected as being highly predictive rather than statistically significant, 544 disease-associated variants were shown to be significantly shared between males and females, which represents a replication in an independent dataset.